Processes for the preparation of 2-aminomethylpyridines and the 2-cyanopyridines used in their preparation

ABSTRACT

Disclosed herein is a process for the preparation of a compound of the formula (II): 
                         
or a salt thereof, wherein X is halogen; each Y, which may be the same or different, is halogen, haloalkyl, alkoxycarbonyl or alkylsulphonyl, and n is 0 to 3;
 
which process comprises treating a compound of the formula (III):
 
                         
with a cyanide source and a catalyst selected from the group consisting of a tetraalkyl ammonium salt and a tetraalkyl phosphonium salt in an aqueous solvent or without solvent, wherein:
 
X is halogen; each Y, which may be the same or different, is halogen, haloalkyl, alkoxycarbonyl or alkylsulphonyl: and n is 0 to 3; and wherein the cyanide source is hydrogen cyanide, an alkali metal cyanide, an alkaline earth metal cyanide or an optionally substituted ammonium cyanide.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 10/362,728, filed Jun. 11, 2003, now U.S. Pat. No. 6,921,828,in the name of Norman DANN, et al., and entitled “PROCESS FOR THEPREPARATION OF 2-AMINOMETHYLPYRIDINES AND THE 2-CYANOPYRIDINES USED INTHEIR PREPARATION”, which in turn, is a 35 U.S.C. § 371 national phaseconversion of International Application No. PCT/EP01/10984 filed Aug.21, 2001, which claims priority of each of the followingforeignapplications: GB Application No. 0021066.6 filed Aug. 25, 2000, GBApplication No. 0025616.4 filed Oct. 19, 2000 and EP Application No.01420128.9 filed Jun. 7, 2001.

This invention relates to novel processes for the preparation of2-aminomethylpyridines (particularly2-aminomethyl-3-chloro-5-trifluoromethylpyridine), and for thepreparation of 2-cyanopyridines used in their preparation, whichcompounds are useful as intermediates for the production of pesticides.

The catalytic reduction of cyanopyridines to give aminomethylpyridinesis known. However when the cyanopyridine compounds contain additionalhalogen atom(s) the reduction may be complicated by the competingdehalogenation reaction. It is stated by P. N. Rylander, HydrogenationMethods (Best Synthetic Series, published by Academic Press), (1985),page 148, that palladium is usually the catalyst of choice when wishingto effect a dehalogenation reaction, and that platinum and rhodium arerelatively ineffective and are hence often used in hydrogenations wherethe halogen is to be preserved.

In contrast with the above prior art teaching we have found that the useof a palladium catalyst gives particularly good results in the reductionof cyanopyridines which contain additional halogen atom(s). We havedeveloped a new process for the preparation of 2-aminomethylpyridines,which contain additional halogen atom(s) in which minimal dehalogenationoccurs, and which is applicable to industrial scale processes.

There have been a number of procedures published for introducing a cyanogroup at the 2-position of a pyridine moiety. These typically involvesubstitution of a halogen, in particular bromine or fluorine, in a polarsolvent, e.g. dimethyl sulplioxide or dimetilylformainide. In addition,there are numerous methods starting from the activated pyridine N-oxideor N-alkylpyridine. Many of these cyanation routes use heavy metalreagents, containing copper or nickel. For example, EP0034917 disclosesthe preparation of 2-cyano-3-chloro-5-trifluoromethylpyridine from the2-bromo analogue by reaction with cuprous cyanide in dimethylformamideat 120° C.

However, many of these prior art processes suffer from one or moredrawbacks, including poor yields, use of heavy metals which producetoxic effluents, or polar solvents which are difficult to recover.Further, methods which involve formation of the pyridine N-oxide orN-alkylpyridine involve several steps. These drawbacks are more criticalon scale-up to industrial scale.

International Patent Application No. WO 01/17970 describes the cyanationof 2-halopyridine compounds with an activating agent and a cyanidesource in a polar solvent and thus avoids many of the abovedisadvantages. However there still remains with this procedure the needto recycle the activating agent and the aprotic solvent in order tominimize the costs for an industrial scale process.

We have now developed an alternative and improved process for thepreparation of 2-cyanopyridines which is applicable to industrial scaleprocesses.

According to a first aspect of the present invention, there is provideda process (A) for the preparation of a compound of general formula (I):

or a salt thereof, which process comprises the catalytic hydrogenationof a compound of general formula (II):

or a salt thereof,wherein X is halogen; each Y, which may be the same or different, ishalogen, haloalkyl, alkoxycarbonyl or alkylsulphonyl; and n is 0 to 3.

In this invention halogen means a fluorine, chlorine or bromine atom.The preferred halogen atom is chlorine.

Haloalkyl typically means a C₁ to C₆ alkyl moiety substituted by one ormore halogen atoms. For example the C₁ to C₆ alkyl moiety may be methyl,ethyl, n-propyl or i-propyl, preferably methyl. The C₁ to C₆ alkylmoiety is preferably substituted by one or more chlorine or fluorineatoms. A more preferred haloalkyl group is trifluoromethyl.

An alkoxycarbonyl group is typically C₁ to C₆ alkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or i-propoxycarbonyl.

An alkylsulphonyl group is typically C₁ to C₆ alkylsulphonyl in whichthe C₁ to C₆ moiety is as defined above.

Preferably X is chlorine.

Preferably Y is halogen or haloalkyl (more preferably trifluoromethyl).

Compound (II) is preferably 3-chloro-2-cyano-5-trifluoromethylpyridine.

The catalyst generally comprises a metal selected from palladium,platinum, ruthenium, nickel and cobalt. The amount of metal in thecatalyst used (which is generally supported on for example charcoal) isgenerally from 0.05-0.7% by weight relative to the amount of thecompound of formula (II), preferably from 0.05-0.3%, more preferablyfrom 0.1-0.2%. A preferred catalyst contains palladium, for examplefinely divided palladium on an inert carrier such as charcoal. This hasbeen found to give both a convenient reaction rate and minimal sidereactions. Thus when the compound of formula (II) is3-chloro-2-cyano-5-trifluoromethylpyridine, minimal dechlorinationoccurs when using the process of the invention. Other examples ofsuitable catalysts include catalysts comprising oxides or othercompounds of the above mentioned metals.

The process is typically carried out in the presence of a solvent suchas an alcohol, for example methanol, ethanol, propanol or butanol, or anester such as ethyl acetate, or an ether such as tetrahydrofuran.Alcohol solvents are preferred (methanol is most preferred). The processis preferably performed in the presence of a strong acid such ashydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid(preferably hydrochloric acid). The presence of the acid helps preventpoisoning of the catalyst by the amino group of the product of formula(I), and also prevents the coupling of amino intermediates which isotherwise known to occur during the catalytic hydrogenation of nitrites.

The reaction conditions typically comprise combining all reactants in asuitable reaction vessel and stirring, for example at a temperature offrom 0 to 60° C., preferably from 20 to 30° C. A further advantage ofthe process is that low pressures are used, with a hydrogen pressure offrom 1 to 4 atmospheres generally being employed (the process ispreferably performed at 1 atmosphere).

The reaction is optionally performed in the presence of a catalystinhibitor, which can lead to a further improvement in the reactionselectivity by reducing the amount of dehalogenation which may occur asa side reaction. Such catalyst inhibitors are known in the art, forexample as described in P. N. Rylander in Hydrogenation Methods (BestSynthetic Series, published by Academic Press),1985, pages 125-126, andinclude alkali metal bromides or iodides such as potassium bromide andpotassium iodide; or ammonium bromide or ammonium iodide; or hydrogenbromide or hydrogen iodide; or phosphorus compounds such as triphenylphosphite, hypophosphorous acid, phosphorous acid or alkylphosphinicacids; or thiodiglycol (2,2′-thiodiethanol); or thiourea; or sulphur.Preferably the catalyst inhibitor is selected from an alkali metalbromide or iodide, ammonium bromide or iodide and hydrogen iodide.

The present invention thus provides a high yielding, selective andconvenient process for the preparation of 2-aminomethylpyridines.

It is particularly convenient to generate the compound of formula (I) inthe form of a salt, especially a hydrochloride salt. When used as anintermediate in the production of a pesticide the salt can be submitteddirectly to the next reaction step without prior isolation of thecorresponding free amine. The production of the salt and its subsequentreaction can therefore be conveniently carried out in a single vessel. Aparticularly preferred salt is2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride.

According to a further feature of the present invention, there isprovided a process (B) for the preparation of a compound of generalformula (II) as defined above which comprises treating a compound ofgeneral formula (III):

with a cyanide source and a catalyst in an aqueous solvent or withoutsolvent,wherein X, Y and n are as hereinbefore defined; and wherein the cyanidesource is hydrogen cyanide, an alkali metal cyanide, an alkaline earthmetal cyanide or an optionally substituted ammonium cyanide.

The catalyst is generally a phase transfer catalyst such as a tetraalkylammonium salt such as benzyl trimethylammonium chloride,tricaprylylmethylammonium chloride, tetramethylammonium chloride,tetra-n-propylammonium bromide, n-dodecyl trimethylammonium chloride,tetra-n-butylammonium chloride, tetra-n-butylammonium bromide,tetra-n-octylammonium bromide or n-tetradecyl trimethylammonium bromide;or a tetraalkyl phosphonium salt such as tetra-n-butylphosphoniumbromide or tetraphenylphosphonium bromide; or a crown ether or acyclicanalogue thereof such as TDA-1 (tris[2-(2-methoxyethoxy)ethyl]amine); oran amine such as 4-dimethylaminopyridine.

Preferably the catalyst is selected from tricaprylylmethylammoniumchloride and tetra-n-octylammonium bromide.

The amount of catalyst used is generally from about 0.01 to 10 mol %,preferably from about 0.1 to 5 mol %, more preferably from about 1 to 5mol %.

Compound (III) is preferably3-chloro-2-fluoro-5-trifluoromethylpyridine.

The above process (B) of the invention is a high yielding process forthe preparation of 2-cyanopyridines, which is simple to perform andoperates at moderate temperatures and does not suffer from the drawbacksof many prior art processes. In particular the process of the inventiondoes not require heavy metal cyanides such as copper or nickel cyanide,which, when used on an industrial scale, produce toxic effluent streamsand are difficult to recover. The process (B) of the invention produceswaste streams, which are readily treatable.

In addition, the process does not require the preparation of activatedpyridine N-oxide or N-alkylpyridine for high conversions, which is arequisite for many of the prior art processes. The process (B) of theinvention does not require an activating agent such as4-dimethylaminopyridine and hence avoids additional recovery andrecycling steps. A further advantage of the process (B) of the inventionis that organic solvents are not used in the reaction, thus avoiding theneed to recycle expensive solvents such as dimethyl sulphoxide.

The cyanide source is preferably sodium cyanide or potassium cyanide,preferably potassium cyanide. The amount of cyanide source used isgenerally from about 1.0 to about 2.0 molar equivalents (however moremay be used if desired), preferably from 1.0 to 1.5 molar equivalents,more preferably from 1.0 to 1.1 molar equivalents.

The reaction is generally and preferably performed using water assolvent, however it may also be carried out in the absence of solvent.

The reaction conditions typically comprise combining all reactants in asuitable reaction vessel and stirring at a temperature of from 10 to 60°C., preferably from 20 to 40° C.

The present invention thus provides a high yielding process (B) for thepreparation of 2-cyanopyridines. Since the reaction uses moderatereaction temperatures, simple and inexpensive reactors and downstreamprocessing equipment is all that is required. Furthermore, since thereactants are readily available, the process is inexpensive to operate.In addition, the present process produces waste streams that are readilytreatable.

According to a further feature of the invention the processes (B) and(A) can be combined to prepare a compound of formula (I) from a compoundof formula (III).

According to a further feature of the invention the process (A), or thecombined processes (B) and (A), is followed by a further process step(C) which comprises the acylation of said compound (I) with a benzoylcompound of formula (IV):

wherein L is a leaving group; R¹ and R² each represent the same ordifferent halogen; and m is 0, 1 or 2, to give a compound of formula(V):

Preferably L is chlorine.

Compounds of Formula (v) are valuable pesticide active ingredientsdisclosed for example in International Patent Publication Number WO99142447.

Preferred compounds of formula (V) are:

-   -   N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2,6-dichlorobenzamide;    -   N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2,6-difluorobenzamide;    -   N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2-chloro-6-fluorobenzamide;    -   N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2,3-difluorobenzamide;    -   N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2,4,6-trifluorobenzamide        or    -   N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2-bromo-6-chlorobenzamide.

Process step (C) is described in International Patent Publication NumberWO 99/42447.

According to a further feature of the invention the process (B), or thecombined processes (B) and (A), or (B), (A) and (C) can be combined withan earlier process step (D) which comprises the fluorination of acompound of formula (VI):

wherein X, Y and n are as defined above.

The process step (D) is generally performed using a suitablefluorinating agent such as an alkali metal fluoride, preferablypotassium fluoride or sodium fluoride, in an aprotic solvent such asdimethyl sulphoxide or sulpholane, at a temperature of from 50° C. to150° C.

The compounds of formula (I) and (II) obtained by the above processes ofthe invention are particularly useful in the preparation of fungicidallyactive 2-pyridylmethylamine derivatives of formula (V), according to thefollowing reaction scheme:

The present invention is farther illustrated by the followingpreparative examples:

EXAMPLE 1 Process Step A

A mixture of 3-chloro-2-cyano-5-trifluoromethylpyridine (5.1 g) and 5%palladium on charcoal (5.1 mg as Pd metal) was stirred at 20° C. withmethanol and concentrated hydrochloric acid (2.5 ml) under 1 atmosphereof hydrogen. After 4 hours the reaction was judged to be complete byhplc. The mixture was filtered through Celatom, washed with methanol andwater and evaporated to give2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride in 95-97%yield, NMR (in D₂O) 4.6 (s, 2H), 8,35 (s, 1H), 8.9 (s, 1H).

EXAMPLE 2 Process Step B

A solution of potassium cyanide (71.6 g) in water (215 g) was addedduring 1 hour to a stirred mixture of3-chloro-2-fluoro-5-trifluoromethylpyridine (199.5 g) and Aliquat 336(tricaprylylmethylammonium chloride, 12.1 g) at 30° C. Stirring wasmaintained at this temperature for 4 hours at which time the amount ofstarting fluoride was less than 1% by hplc. The lower organic phase wasseparated and washed with aqueous sodium chloride solution and distilledto give 3-chloro-2-cyano-5-trifluoromethylpyridine (185.8 g, 90% yield)bp 90° C. at 15 mbar. The purity of this product was 98%.

EXAMPLE 3 Process Step B

Solid sodium cyanide (0.29 g) was added to a stirred mixture of3-chloro-2-fluoro-5-trifluoromethylpyridine (0.8 g) andtetrabutylammonium bromide (0.06 g) at 20-25° C., and stirred for 23hours to give 3-chloro-2-cyano-5-trifluoromethylpyridine (0.68 g, 82%yield by hplc).

Example of Process Step (D)

2,3-Dichloro-5-trifluoromethylpyridine (800 g) was added to a stirredmixture of anhydrous potassium fluoride (320 g) and anhydrousdimethylsulphoxide at 110° C. then heated at 120° C. for 2 hours andfractionally distilled under reduced pressure to give3-chloro-2-fluoro-5-trifluoromethylpyridine (685 g) in a yield of 92%(98% purity).

1. A process for the preparation of a compound of the formula (II):

or a salt thereof, wherein X is halogen; each Y, which may be the sameor different, is halogen, haloalkyl, alkoxycarbonyl or alkylsulphonyl,and n is 0 to 3; which process comprises treating a compound of theformula (III):

with a cyanide source and a catalyst selected from the group consistingof a tetraalkyl ammonium salt and a tetraalkyl phosphonium salt in anaqueous solvent or without solvent, wherein: X is halogen; each Y, whichmay be the same or different, is halogen, haloalkyl, alkoxycarbonyl oralkylsulphonyl: and n is 0 to 3; and wherein the cyanide source ishydrogen cyanide, an alkali metal cyanide, an alkaline earth metalcyanide or an optionally substituted ammonium cyanide.
 2. A processaccording to claim 1, in which the catalyst is selected fromtricaprylylmethylammonium chloride and tetra-n-octylammonium bromide. 3.A process according to claim 1 in which the amount of catalyst used isfrom 0.01 to 10 mol %.
 4. A process according to claim 1 in which thecyanide source is potassium cyanide.
 5. A process according to claim 1in which the amount of cyanide source used is from 1.0 to 2.0 molarequivalents.
 6. A process according to claim 1 in which the solvent iswater.
 7. A process according to claim 1 in which the temperature isfrom 10 to 60° C.
 8. A process according to claim 1 in which thecompound of formula (III) is3-chloro-2-fluoro-5-trifluoromethylpyridine.